Typical antipsychotic
Template:Short description Template:Infobox drug class
Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously.<ref>Template:Cite journal</ref> Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders with typical antipsychotics.
Both generations of medication tend to block receptors in the brain's dopamine pathways, but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause extrapyramidal symptoms (EPS), which include unsteady Parkinson's disease-type movements, internal restlessness, and other involuntary movements (e.g. tardive dyskinesia, which can persist after stopping the medication).<ref>Template:Cite journal</ref> More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal The Lancet to write in its editorial "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction."<ref>Template:Cite journal</ref> While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause adverse metabolic effects, such as weight gain and increase the risk for type II diabetes.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Clinical usesEdit
Typical antipsychotics block the dopamine 2 receptor (D2) receptor, causing a tranquilizing effect.<ref name="Schatzberg 2019">Template:Cite book</ref> It is thought that 60–80% of D2 receptors need to be occupied for antipsychotic effect.<ref name="Schatzberg 2019" /> For reference, the typical antipsychotic haloperidol tends to block about 80% of D2 receptors at doses ranging from 2 to 5 mg per day.<ref name="Schatzberg 2019" /> On the aggregate level, no typical antipsychotic is more effective than any other, though people will vary in which antipsychotic they prefer to take based on individual differences in tolerability and effectiveness.<ref name="Schatzberg 2019" /> Typical antipsychotics can be used to treat, e.g., schizophrenia or severe agitation.<ref name="Schatzberg 2019" /> Haloperidol, due to the availability of a rapid-acting injectable formulation and decades of use, remains the most commonly used antipsychotic for treating severe agitation in the emergency department setting.<ref name="Schatzberg 2019" />
Adverse effectsEdit
Adverse effects vary among the various agents in this class of medications, but common effects include: dry mouth, muscle stiffness, muscle cramping, tremors, EPS and weight gain. EPS refers to a cluster of symptoms consisting of akathisia, parkinsonism, and dystonia. Anticholinergics such as benztropine and diphenhydramine are commonly prescribed to treat the EPS. 4% of users develop rabbit syndrome while on typical antipsychotics.<ref name="2870650PMID">Template:Cite journal</ref>
There is a risk of developing a serious condition called tardive dyskinesia as a side effect of antipsychotics, including typical antipsychotics. The risk of developing tardive dyskinesia after chronic typical antipsychotic usage varies on several factors, such as age and gender, as well as the specific antipsychotic used. The commonly reported incidence of TD among younger patients is about 5% per year. Among older patients incidence rates as high as 20% per year have been reported. The average prevalence is approximately 30%.<ref>Template:Cite journal</ref> There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an VMAT2 inhibitor like valbenazine may help.<ref name="FDA approves valben">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The atypical antipsychotic clozapine has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia.<ref name="Pardis et al 2019">Template:Cite journal</ref> Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Full citation needed</ref>
Neuroleptic malignant syndrome (NMS) is a rare, but potentially fatal side effect of antipsychotic treatment. NMS is characterized by fever, muscle rigidity, autonomic dysfunction, and altered mental status. Treatment includes discontinuation of the offending agent and supportive care.
The role of typical antipsychotics has come into question recently as studies have suggested that typical antipsychotics may increase the risk of death in elderly patients. A 2005 retrospective cohort study from the New England Journal of Medicine showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics.<ref>Template:Cite journal</ref> This has led some to question the common use of antipsychotics for the treatment of agitation in the elderly, particularly with the availability of alternatives such as mood stabilizing and antiepileptic drugs.
PotencyEdit
Traditional antipsychotics are classified as high-potency, mid-potency, or low-potency based on their potency for the D2 receptor:
| Potency | Examples | Adverse effect profile |
|---|---|---|
| high | fluphenazine and haloperidol | more extrapyramidal side effects (EPS) and less antihistaminic effects (e.g. sedation), alpha adrenergic antagonism (e.g. orthostatic hypotension), and anticholinergic effects (e.g. dry mouth) |
| middle | perphenazine and loxapine | intermediate D2 affinity, with more off-target effects than high-potency agents |
| low | chlorpromazine | less risk of EPS but more antihistaminic effects, alpha adrenergic antagonism, and anticholinergic effects |
Prochlorperazine (Compazine, Buccastem, Stemetil) and Pimozide (Orap) are less commonly used to treat psychotic states, and so are sometimes excluded from this classification.<ref name="isbn0-684-82737-9">Template:Cite book</ref>
A related concept to D2 potency is the concept of "chlorpromazine equivalence", which provides a measure of the relative effectiveness of antipsychotics.<ref name="pmid12823080">Template:Cite journal</ref><ref name="pmid14624195">Template:Cite journal</ref> The measure specifies the amount (mass) in milligrams of a given drug that must be administered in order to achieve desired effects equivalent to those of 100 milligrams of chlorpromazine.<ref name="Patel et al 2013">Template:Cite journal</ref> Another method is "defined daily dose" (DDD), which is the assumed average dose of an antipsychotic that an adult would receive during long-term treatment.<ref name="Patel et al 2013" /> DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics.<ref name="Patel et al 2013" /> Maximum dose methods are sometimes used to compare between antipsychotics as well.<ref name="Patel et al 2013" /> It is important to note that these methods do not generally account for differences between the tolerability (i.e. the risk of side effects) or the safety between medications.<ref name="Patel et al 2013" />
For a list of typical antipsychotics organized by potency, see below:
Low potencyEdit
Medium potencyEdit
High potencyEdit
- Droperidol
- Flupentixol
- Fluphenazine
- Haloperidol
- Pimozide
- Prochlorperazine
- Thioproperazine
- Trifluoperazine
- Zuclopenthixol
Template:End div col †: discontinued or withdrawn products<ref>Template:Cite book</ref>
Long-acting injectablesEdit
Some typical antipsychotics have been formulated as a long-acting injectable (LAI), or "depot", formulation. Depot injections are also used on persons under involuntary commitment to force compliance with a court treatment order when the person would refuse to take daily oral medication. This has the effect of dosing a person who doesn't consent to take the drug. The United Nations Special Rapporteur On Torture has classified this as a human rights violation and cruel or inhuman treatment.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
The first LAI antipsychotics (often referred to as simply "LAIs") were the typical antipsychotics fluphenazine and haloperidol.<ref name="Kennedy 2012">Template:Cite journal</ref> Both fluphenazile and haloperidol are formulated as decanoates, referring to the attachment of a decanoic acid group to the antipsychotic molecule.<ref name="Kennedy 2012" /> These are then dissolved in an organic oil.<ref name="Kennedy 2012" /> Together, these modifications prevent the active medications from being released immediately upon injection, attaining a slow release of the active medications (note, though, that the fluphenazine decanoate product is unique for reaching peak fluphenazine blood levels within 24 hours after administration<ref name="Carpenter et al 2018">Template:Cite journal</ref>).<ref name="Kennedy 2012" /> Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days),<ref name="Carpenter et al 2018" /> while haloperidol decanoate can be administered every 28 days, though some people receive more or less frequent injections.<ref name="Kennedy 2012" /> If a scheduled injection of either haloperidol decanoate or fluphenazine decanoate is missed, recommendations for administering make-up injectable dose(s) or providing antipsychotics to be taken by mouth vary by, e.g., how long ago the last injection was and how many previous injections the person has received (i.e., if steady state levels of the medication have been reached or not).<ref name="Carpenter et al 2018" />
Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs.<ref name="Kennedy 2012" /> Doctors usually prefer atypical LAIs over typical LAIs due to the differences in adverse effects between typical and atypical antipsychotics in general.<ref name="Carpenter et al 2018" />
Template:Pharmacokinetics of long-acting injectable antipsychotics
HistoryEdit
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The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic after an initial report in 1952.<ref name="Schatzberg 2019" /> It was first used in psychiatric institutions because of its powerful tranquilizing effect; at the time it was advertised as a "pharmacological lobotomy".<ref name=pieters>Template:Cite journal</ref> (Note that "tranquilizing" here only refers to changes in external behavior, while the experience a person has internally may be one of increased agitation but inability to express it.)<ref>Template:Cite journal</ref>
Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.<ref name="king">Template:Cite journal</ref> In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic".<ref name="king"/> The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine.<ref name="king"/> It is derived from the Template:Langx (neuron, originally meaning "sinew" but today referring to the nerves) and "λαμβάνω" (lambanō, meaning "take hold of"). Thus, the word means taking hold of one's nerves. It was often taken to refer also to common effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working.<ref name=pieters /> These terms have been largely replaced by the term "antipsychotic" in medical and advertising literature, which refers to the medication's more-marketable effects.<ref name="king"/>
See alsoEdit
- Tranquilizer
- Atypical antipsychotic
- Tardive dyskinesia
- Schizophrenia
- Bipolar disorder
- Psychiatric survivors' movement
- Conditioned avoidance response test